ES2733552T3 - Procedures for the treatment of obesity by apremilast - Google Patents

Abstract

A compound for use in a method of treating or controlling obesity or overweight, comprising orally administering to an obese patient an effective amount of the compound, where the compound is (+) - 2- [1- (3 stereomerically pure -ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione or one of its pharmaceutically acceptable polymorphs, salts or solvates.

Description

DESCRIPTION

Procedures for the treatment of obesity by apremilast

2. FIELD

This document provides apremilast for use in procedures to treat, prevent and / or control obesity by administering apremilast, alone or in combination with other treatments or therapeutic regimens. Herein, pharmaceutical compositions and dosage forms are also provided comprising specific amounts of apremilast suitable for use in obesity treatment, prevention and / or control procedures.

3. BACKGROUND

Obesity is a major public health crisis in the United States and internationally, and the prevalence increases rapidly in many nations. It was reported that the prevalence of obesity among American men and women was almost 36% in 2009 and 2010. See Flegal Km et al., «Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010 »JAMA, 2012, 307 (5): 491-7. Obesity represents a state of excess body fat storage. The term overweight is defined as excess body weight for height. Normal and healthy men have a body fat percentage of 15-20%, while normal and healthy women have a percentage of approximately 25-30%. See Gallagher D et al., "Healthy percentage body fat ranges: an approach for developing guidelines based on body mass index" Am J Clin Nutr., 2000, 72 (3): 694-701. Because differences in weight between individuals are only partly the result of variations in body fat, body weight is a limited index of obesity. The body mass index (BMI) is used much more commonly than the percentage of body fat to define obesity.

The most widely accepted classifications for obesity grades are those of the World Health Organization (WHO), based on body mass index (BMI). WHO designations are as follows: Grade 1 overweight (common and simply called overweight): BMI of 25-29.9 kg / m2

Grade 2 overweight (commonly called obesity): BMI of 30-39.9 kg / m2

Grade 3 overweight (commonly called severe or morbid obesity): BMI> 40 kg / m2.

Effective approaches to losing weight include lifestyle changes, such as diet, physical activity and behavioral counseling. Pharmacotherapy is recommended for people who cannot achieve weight loss with lifestyle interventions alone. Nainggolan L, "New obesity guidelines: authoritative 'roadmap' to treatment" Medscape Medical News, nov. 2013 (available at http: //www.medscape. Com / viewarticle / 814202). Currently, medications used to control obesity include centrally acting medications that impair food intake, medications that act peripherally to impair food absorption, and medications that increase energy expenditure.

US 2006/0079540 A1 describes the use of a PDE4 inhibitor for the treatment of cachexia. The clinical picture of cachexia includes weight loss. However, the use of the PDE4 inhibitor described in the publication was not for the treatment of obesity with the intention of inducing weight loss.

A decrease in weight was observed in the treatment of chronic obstructive pulmonary disease (COPD) with roflumilast as a side effect. See Klaus F. Rabe, British Journal of Pharmacology, 2011, 163: 53-67; Stephen K. Field, Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, 2011, 5: 57-70; Kumar et al., BMC Medicine, 2013, 11: 96: 1-8; and Nicola J. Sinden et al., Ther Adv Chronic Dis, 2010, 1 (2): 43-57. Weight loss is frequently observed in patients with COPD, especially when their disease worsens, as they often have difficulty eating when they are out of breath. Id.

In contrast to the weight loss observed as a side effect in COPD patients treated with another PDE4 inhibitor, the apremilast in the present invention provides weight loss benefits to patients with an average BMI of 30 or more, which is the clinical definition of obesity.

4. SUMMARY

In this document, apremilast or a pharmaceutically acceptable polymorph, salt or solvate thereof is provided for use in procedures to treat, prevent and / or control obesity or overweight in humans who need it. The invention comprises administering to a patient in need of such treatment, prevention or management with a therapeutically or prophylactically effective amount of apremilast, or a pharmaceutically acceptable metabolite, polymorph, salt, solvate ( eg hydrate) or clathrate thereof.

In some embodiments, it is provided in this document. (+) - 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione stereomerically pure, or a pharmaceutically acceptable product. polymorph, salt or solvate thereof for use in a procedure to treat, prevent and / or control obesity or overweight, which comprises administering to the oral route a patient who is obese or overweight an effective amount of (+) - 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione stereomerically pure, or one of its pharmaceutically acceptable polymorphs, salts or solvates.

In some embodiments, the patient is administered approximately 10 mg twice daily (BID) of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl-1] -4-acetylaminoisoisoindindin- Stereomerically pure 1,3-dione, or a pharmaceutically acceptable polymorph, salt, or solvate thereof. In some embodiments, the dose is approximately 20 mg BID. In other embodiments, the dose is approximately 30 mg BID. In some embodiments, the dose is approximately 40 mg BID or 80 mg once daily (QD).

In some embodiments, stereomerically pure (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, or a pharmaceutically acceptable polymorph, salt or solvate thereof is administered orally in a dosage form, such as a tablet and a capsule.

In some embodiments, the invention further comprises the administration of a therapeutically or prophylactically effective amount of one or more second active agents. Examples of the second active agents include, among others, phentiramine, lorcaserin, topiramate, orlistat or other approved weight loss medications. In some embodiments, the second active agents include, but are not limited to, an analgesic, a nonsteroidal anti-inflammatory drug ( i.e., NSAID), an anti-inflammatory agent, a COX-2 inhibitor, an opioid, a corticosteroid, a biological agent, and an immunosuppressant.

In some embodiments, the invention further comprises other measures of weight reduction, such as changes in dietary habits, exercise programs or psychological support programs.

5. DETAILED DESCRIPTION

5.1 Definitions

As used herein, the term "apremilast" refers to (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindindin-1,3-dione, also known as N- [2 - [(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -2,3-dihydro-1,3-dioxo-1H-isoindole-4 -ilo] acetamide. The apremilast has the following structure:

Without being limited by theory or mechanism of action, Apremilast is a phosphodiesterase 4 (PDE4) inhibitor, and works intracellularly to modulate a network of pro- and anti-inflammatory mediators. Phosphodiesterase 4 is a phosphodiesterase (PDE) specific for adenosine monophosphate (cAMP) and the dominant PDE in inflammatory cells. Inhibition of PDE4 increases levels of intracellular cAMP, which, in turn, regulates the inflammatory response by modulating the expression of tumor necrosis factor alpha (TNF-a), interleukin (IL) -23 and other inflammatory cytokines. The elevation of cAMP also increases anti-inflammatory cytokines such as IL-10. These pro and anti-inflammatory mediators have been implicated in psoriasis and psoriatic arthritis. See, for example, Schafer et al., "Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis," Br. J. Pharmacol., 2010,159 (4): 842 -55.

Adipocyte-specific lipin 1 and mitochondrial dysfunction may be involved in the mechanism of weight loss, so that the apremilast can increase lipogenesis and basal metabolic activity, through inhibition of PDE4 and elevation of the protein kinase A and activation of the CREB pathway (cAMP sensitive element binding protein). See Aurelia De Pauw et al., The American Journal of Pathology, September 2009, Vol. 175, No. 3: 927-939; and Mayurranjan S. Mitra et al., PNAS, 2013, vol. 110, No. 2: 642-647.

Apremilast is in clinical development for the treatment of autoimmune inflammatory disorders in adults that involve high levels of cytokines, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, Behpet's disease and ankylosing spondylitis.

As used herein and unless otherwise indicated, the term "pharmaceutically salt Acceptable »includes, but is not limited to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts provided herein include metal salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts of lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine , meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, organic and inorganic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, etensulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic acids. , hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulphanilic, sulfuric, tartaric and p-toluenesulfonic. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids. Examples of specific salts therefore include hydrochloride and mesylate salts. As used herein and, unless otherwise indicated, the term "hydrate" means a compound provided herein or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of water bound by intermolecular forces. not covalent

As used herein and, unless otherwise indicated, the term "solvate" means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term "solvate" includes hydrates ( for example, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein and, unless otherwise indicated, the term "polymorph" means solid crystalline forms of a compound provided herein or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical, pharmacological and / or spectroscopic properties.

As used herein, and unless otherwise specified, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize or otherwise react under biological conditions ( in vitro or in vivo) to provide the compound. . Examples of prodrugs include, but are not limited to, derivatives and metabolites of apremilast that include biohydrolysable moieties such as biohydrolysable amides, biohydrolysable esters, biohydrolysable carbamates, biohydrolysable carbonates, biohydrolysable ureides and biohydrozable phosphate analogs. Generally, prodrugs can be prepared using known procedures, such as those described by 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.

nineteen ninety five).

As used herein, and unless otherwise specified, the term "stereoisomer," "isomer," or "stereoisomer" encompasses all enantiomerically / stereomerically pure and enantiomerically / stereomerically enriched compounds provided herein.

As used herein, and unless otherwise indicated, the term "stereomerically pure" or "enantiomerically pure" means that a compound comprises a stereoisomer and is substantially free of its counter-stereoisomer or enantiomer. For example, a compound is stereomeric or enantiomerically pure when the compound contains greater than or equal to 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of a stereoisomer and 20% 15% , 10%, 5%, 4%, 3%, 2%, 1% or less of the counter stereoisomer. Substantially free of its (R) enantiomer is encompassed by the expression stereomerically pure or enantiomerically pure. As used herein, the term "adverse effect" includes, but is not limited to gastrointestinal, renal and hepatic toxicities, leukopenia, increases in bleeding times due to, for example , thrombocytopenia, and prolonged pregnancy, nausea. , vomiting, drowsiness, asthenia, dizziness, teratogenicity, extrapyramidal symptoms, acatisia, cardiotoxicity, including cardiovascular disorders, inflammation, male sexual dysfunction and elevated levels of serum liver enzymes. The term "gastrointestinal toxicities" includes, but is not limited to erosions and gastric and intestinal ulcerations. The term "renal toxicities" includes, but is not limited to conditions such as papillary necrosis and papillary necrosis and chronic interstitial nephritis. As used herein, the term "patient" refers to a mammal, particularly a human being. In some embodiments, the patient is a woman. In other embodiments, the patient is a man. In other embodiments, the patient is a child or a teenager.

As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate an action that occurs while a patient suffers from the specified disease, disorder or condition that reduces the severity or symptoms of the disease, disorder or condition, or delays or slows the progression of the symptoms of the disease, disorder or condition.

As used herein, unless otherwise specified, the terms "prevent", "preventing" and "prevention" contemplate an action that occurs before a patient begins to suffer from the disease, specified disorder or condition, which inhibits or reduces the severity or symptoms of the disease, disorder or condition.

As used herein, and unless otherwise indicated, the terms "administer", "administering" and "administration" encompass the prevention of the recurrence of the specified disease, disorder or condition in a patient who has already suffered from the disease, disorder or condition and / or lengthening of the time in which a patient who has suffered from the disease, the disorder or condition remains in remission. The terms include modulating the threshold, development and / or duration of the disease, disorder or condition or changing the way in which the patient responds to the disease, disorder or condition.

5.2 Compounds for use in treatment procedures

Compounds are provided herein for use in procedures to treat, control and / or prevent obesity or overweight, which comprise administering to a patient in need of such treatment, control or prevention a therapeutic or prophylactically effective amount of apremilast, or a pharmaceutically acceptable metabolite, polymorph, salt, solvate or clathrate.

In some embodiments, the invention also encompasses inhibiting or avoiding the symptoms of obesity, as well as addressing the disease itself, before the onset of symptoms by the administration of apremilast, or a metabolite, polymorph, salt, solvate or clathrate of the same pharmaceutically acceptable.

In some embodiments, (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione stereomerically pure, or a polymorph, salt is provided herein. or pharmaceutically acceptable solvate thereof for use in a procedure to treat obesity or reduce weight, which comprises administering to an oral patient to an obese or overweight patient an effective treatment amount of (+) - 2- [1- ( Stereomerically pure 3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, or one of its pharmaceutically acceptable polymorphs, salts or solvates.

In certain embodiments, the apremilast is administered orally to a patient who is obese or overweight at a dose of approximately 10 mg, 20 mg, 30 mg or 40 mg twice daily. In certain embodiments, apremilast can be used only in doses of 20 mg, 30 mg or 40 mg twice daily (IDB), or in combination with other weight reduction measures, such as changes in eating habits, exercise programs or psychological support programs. Weight loss can be observed within a few months of administration and can progress with continued use.

In some embodiments, the patient is administered approximately 10 mg twice daily (BID) of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl-1] -4-acetylaminoisoisoindindin- Stereomerically pure 1,3-dione, or a pharmaceutically acceptable polymorph, salt or solvate thereof. In some embodiments, the dose is approximately 20 mg BID. In other embodiments, the dose is approximately 30 mg BID. In other embodiments, the dose is approximately 40 mg BID.

In some embodiments, stereomerically pure (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione, or a pharmaceutically acceptable polymorph, salt or solvate thereof is administered orally in a dosage form, such as a tablet and a capsule.

In certain embodiments, apremilast is administered orally to an obese patient at an initial dose of approximately 10 mg, 20 mg, 30 mg or 40 mg twice daily. In some embodiments, the maximum daily dose is about 20 mg to about 40 mg. In some embodiments, the maximum daily dose is about 30 mg to about 60 mg. In some embodiments, the maximum daily dose is about 40 mg to about 100 mg.

In some embodiments, the stereomerically pure (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione comprises more than about 90% by weight of the (+) isomer based on the total weight percentage of the compound.

In some embodiments, the stereomerically pure (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione comprises more than about 95% by weight of the (+) isomer based on the total weight percentage of the compound.

In some embodiments, the stereomerically pure (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione comprises more than about 96% by weight of the (+) isomer based on the total weight percentage of the compound.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione stereomerically comprises more than about 97% by weight of the isomer (+) based on the percentage in total weight of the compound.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphene) -2-methalsulfonletlet] -4-acetylaminenoisolendol! Stereomerically pure n-1,3-done comprises more than about 98% by weight of the (+) somer based on the percentage by weight of the compound.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done comprises more than about 99% by weight of the (+) somer based on the percentage by weight of the compound.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered in an amount of approximately 20 mg twice daily following the null program.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered in an amount of approximately 30 mg twice daily following the null program.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered in an amount of approximately 40 mg twice a day following the null program.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered once or twice daily.

In some embodiments, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered as a tablet. In some embodiments, the tablet comprises a dose of 10 mg, 20 mg, 30 mg or 40 mg of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyllet L] -4-Acetylamine or indole-1,3-done stereomerically pure.

In some embodiments, the tablet further comprises lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. In some embodiments, the tablet further comprises red iron oxide. In some embodiments, the tablet further comprises yellow iron oxide. In some embodiments, the tablet further comprises black iron oxide.

In one embodiment, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonletlet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered as a tablet comprising a 10 mg dose of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2 -methylsulfon¡let¡l] -4-acet¡lam¡no¡so¡ndol¡na-1,3-donaona stereomerically, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide , polyethylene glycol, talc and red iron oxide.

In one embodiment, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonletlet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered as a tablet comprising a dose of 20 mg of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2 -methylsulfon¡let¡l] -4-acet¡lam¡no¡so¡ndol¡n-1,3-done stereomerically pure, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, dioxide titanium, polyethylene glycol, talc, red iron oxide and yellow iron oxide.

In one embodiment, the (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonletlet] -4-acetyllamine or soolol Stereomerically pure n-1,3-done is administered as a tablet comprising a dose of 30 mg of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2 -methylsulfon¡let¡l] -4-acet¡lam¡no¡so¡ndol¡n-1,3-done stereomerically pure, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, dioxide titanium, polyethylene glycol, talc and iron oxide red, iron oxide yellow and iron oxide black.

In some embodiments, the invention provided herein further comprises administering to the patient a therapeutically effective amount of a second active agent. In some embodiments, the invention further comprises the administration of a therapeutically effective amount of medicaments available for the treatment of obesity, including, but not limited to, gastrointestinal agents ( e.g., orlistat), CNS stimulants and anorexigenics ( p eg, lorcaserin, topiramate, phentermine), diethylpropione, phendimetrazine and benzfetamine).

In some embodiments, the invention further comprises the administration of a therapeutically or prophylactically effective amount of one or more second active agents, including, but not limited to, an analgesic, an anti-inflammatory agent, a COX-2 inhibitor, a opioid, a corticosteroid, a biological agent and an immunosuppressant. In some embodiments, the second active agent is a non-steroidal anti-inflammatory drug ( ie, NSAIDs such as celecoxib, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen and piroxicam). In some embodiments, the second active agent is a disease-modifying anti-rheumatic drug ( ie, DMARD, such as methotrexate, leflunomide, sulfasalazine and hydroxychloroquine).

In some embodiments, the invention further comprises other measures of weight reduction, such as changes in dietary habits, exercise programs or psychological support programs.

In some embodiments, the patient has received prior treatment for obesity or arthritis. In some embodiments, the patient is relapsed or refractory to prior treatment.

In some embodiments, the invention comprises administering (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindindin-1,3-dione stereomerically pure, substantially free of any form of (+) - 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione salt or solvate.

In some embodiments, the invention comprises administering a pharmaceutically acceptable salt of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindindin-1,3-dione stereomerically pure.

In some embodiments, the invention comprises the administration of a pharmaceutically acceptable solvate of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoisoindindin-1,3-dione .

5.2.1 Combination therapy

In particular embodiments, apremilast is administered in combination with another drug ("second active agent") to treat, control and / or prevent obesity.

In certain embodiments, the invention encompasses synergistic combinations for the treatment, prevention and / or management of obesity. Apremilast can also be used to relieve the adverse effects associated with some second active agents.

One or more second active agents can be used in the invention together with apremilast. The second active agents can be administered before, after or simultaneously with premilast. In some embodiments, the invention comprises the administration of a therapeutically effective amount of medicaments for treating obesity, including, but not limited to, gastrointestinal agents ( e.g., orlistat), CNS stimulants and anorexigenics ( e.g., lorcaserin, phentermine, diethylpropion, phendimetrazine and benzfetamine).

In one embodiment, the second active agent is selected from the group consisting of an anti-inflammatory agent, an immunosuppressant, mycophenolate mofetil, a biological agent or a Cox-2 inhibitor.

In some embodiments, the second active agents may include, but are not limited to anti - inflammatory such as NSAIDS including but not limited to diclofenac (p. G., ARTHROTE ^c ®), diflunisal (p. G., Dolobid®) , etodolac ( e.g., LODINE®), fenoprofen (e.g. , NALFON®), ibuprofen ( e.g., ADVIL, CHILDREN'S ADVIL / MOTRIN, MEDIPREN, MOTRIN, NUPRIN or PEDIACARE FEVER®), indomethacin ( e.g., ARTHREXIN®), ketoprofen ( e.g., ORUVAIL®), ketorolac ( e.g., TORADOL®), fosfomycin tromethamine ( e.g., MONURAL®), meclofenamate ( eg, Meclomen®) , nabumetone ( e.g., RELAFEN®), naproxen ( e.g., ANAPROX®, ANAPROX® DS, EC-NAPROSYN®, NAPRELAN® or NAPROSYN®), oxaprozin ( e.g., DAYPRO®), piroxicam (e.g. , FELDENE®), sulindac ( e.g., CLINORIL®) and tolmetin ( e.g., TOLECTIN® DS or TOLECTIN®).

In other embodiments, the second active agents may include, but are not limited to disease-modifying antirheumatic drugs (DMARD) or immunosuppressants such as, but are not limited to methotrexate (Rheumatrex®), sulfasalazine (Azulfidine®), leflunomide (Arava ®) and cyclosporine (Sandimmune® or Neroal®).

In other embodiments, the second active agent is an oral corticosteroid, such as budesonide (Entocort®), dexamethasone, fludrocortisone (Florinef®, Florinef® acetate), hydrocortisone, methylprednisone, prednisolone and prednisone.

In other embodiments, the second active agents may include, but are not limited to mycophenolate mofetil (CellCept®), an immunosuppressive agent widely used in organ transplantation and gaining ground in the treatment of autoimmune and inflammatory skin disorders.

In further embodiments, the second active agents may include, but are not limited to biological agents such as etanercept (Enbrel®), infliximab (Remicade®) and adalimumab (Humira®).

In other embodiments, the second active agents may include, but are not limited to Cox-2 inhibitors such as celecoxib (Celebrex®), valdecoxib (Bextra®) and meloxicam (Mobic®).

In some embodiments, one or more selective active agents are selected from the group consisting of acitretin, adalimumab, alclomethasone, alefacept, aloe vera, amcinonide, ammonium / urea lactate, ammonium / halobetasol lactate, anthraline, benzine / pyrilamine / zinc oxide, betamethasone, betamethasone / calcipotriene, calcipotriene, clobetasol, alkylcortone, clocortolone salicylic, corticotropin, cyclosporine, desonide, deoxymethasone, diflorasone, fluocinonide, flurandrenolide, halcinonide, halobetasol, hydrocortisone, hydrocortisone / pramoxine, hydroxyurea, infliximab, methotrexate, methoxsalene, predxoroneone, predineoneone, predineoneone, predineoneone, predinecinoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneone, predineoneoneone ustekinumab.

In some embodiments, one or more selective active agents are selected from the group of abatacept, paracetamol, paracetamol / hydrocodone, acetaminophen / tramadol, adalimumab, alemtuzumab, aluminum hydroxide / aspirin / calcium carbonate / magnesium hydroxide, anakinra, aspirin, auranofin , aurothioglucose, atorvastatin, azathioprine, celecoxib, certolizumab, chondroitin, cortisone, corticotropin, cyclophosphamide, cyclosporine, daclizumab, dexamethasone, diclofenac, diclofenac / misoprostol, diflunisal, doxycycline, esomeprazole, esomeprazole / naproxen, etanercept, etodolac, famotidine, famotidine / ibuprofen , fenoprofen, flurbiprofen, glucosamine, gold sodium thiomalate, golimumab, hydroxychloroquine, ibuprofen, indomethacin, infliximab, interferon, interferon gamma-lb, ketoprofen, lansoprazole, lansoprazole / naproxen, leflunomide, levamisole, meclofenamate, meloxicam, methotrexate, methylprednisolone, methylprednisolone , methyl salicylate, minocycline, mycophenolate mofetil, nab umetone, naproxen, oxaprozin, penicillamine, phenytoin, piroxicam, prednisone, evening primrose oil, rituximab, rofecoxib, salsalate, sulindac, sulfasalazine, tetracycline, tocilizumab, tofacitinib, tolmetin, tramadol, triamcinolibyl triacinolone, saltylamine.

In some embodiments, one or more selective active agents are selected from the group consisting of abatacept, acetaminophen, acetaminophen / hydrocodone, acetaminophen / tramadol, acitretin, adalimumab, alclomethasone, alefacept, alemtuzumab, aloe vera, aluminum hydroxide / aspirin / carbonate calcium / magnesium hydroxide, amcinonide, ammonium / urea lactate, ammonium / halobetasol lactate, anakinra, anthralin, aspirin, auranofin, aurothioglucose, atorvastatin, azathioprine, benzocaine / pyrilamine / zinc oxide, betamethasone, betametotriene / calcipotriene celecoxib, certolizumab, chondroitin, clobetasol, clocortolone, tar, alkyl / salicylic acid, corticotropin, cortisone, cyclophosphamide, cyclosporine, daclizumab, desonide, deoxymetasona, dexamethasone, diclofenac, diphthloxamotholone, eslophenoxyaprisone, eslophenoxyaprisone, eslophentaxyl, esophaloxamotholone, eslophenoxamotholone, eslophenoxamotholone, eslophenoxamotholone, esophaloxamotholone, eslophenoxamotholone, eslophenoxyaprinol, naphtholoneamine, naphtholoneamine, naphtholoneamine, naphthioxamotholoneol , etanercept, etodolac, famotidine, famotidine / ibuprofen, fenoprofen, fluocinonide, flurand renolphine, flurbiprofen, phostamatinib, glucosamine, golden sodium thiomalate, golimumab, halcinonide, halobetasol, hydrocortisone, hydrocortisone / pramoxine, hydroxyurea, hydroxychloroquine, ibuprofen, indomethacin, infliximab, interferon, ibophorazin, lbophenol naproxen, leflunomide, lenalidomide, levamisole, meclofenamate, meloxicam, methotrexate, methoxsalen, methylprednisone, methylprednisolone, methyl salicylate, minocycline, mometasone, mycophenolate mofetil, nabumetone, pheproxine, pproxine, pheproxine, pproxine, phenoxy, praproxine, pproxine, phenoxy, praproxine prednisolone, prednicarbate, evening primrose oil, resorcinol, rituximab, rofecoxib, salsalate, sulindac, sulfasalazine, tazarotene, tetracycline, tocilizumab, tofacitinib, tolmetine, tramadol, triamcinolone, trolamine salicylate, ustekinx-3-valdebumab-3 -methyl-4-oxo-4H-quinazolin-3-yl) -piperidin-2,6-dione and (S) -3- (4 - ((4- (morpholinomethyl) benzyl) oxy) -1-oxois oindolin-2-yl) piperidin-2,6-dione.

In some embodiments, one or more selective active agents are selected from the group consisting of a Btk inhibitor, a brain-addressing agent, a Tyk2 inhibitor, a Syk inhibitor, a JNK inhibitor, an MK2 inhibitor, a ERP5 inhibitor, a PD-1 inhibitor, a TIMP-3 inhibitor, an IKK-2 inhibitor, an LH2B inhibitor, a PKC-theta inhibitor, an IRAK4 inhibitor, a ROCK inhibitor and an inhibitor of ROR-gamma-T.

The administration of apremilast and a second active agent to a patient can occur simultaneously or sequentially by the same or different routes of administration. The adequacy of a particular route of administration employed for a particular active agent will depend on the active agent itself ( eg, if it can be administered orally without decomposing before entering the bloodstream) and the cancer being treated. Particular routes of administration for the second active ingredients or ingredients are known to those skilled in the art. See, for example, The Merck Manual, 448 (17th ed., 1999).

The amount of a second active agent administered can be determined based on the specific agent used, the subject being treated, the severity and stage of the disease and the amount (or amounts) of apremilast and any optional additional active agent administered. simultaneously to the patient. Those skilled in the art can determine specific amounts according to conventional procedures known in the art. At first, you can start with the amount of the second active agent that is conventionally used in therapies and adjust the amount according to the factors described above. See, for example, Physician's Desk Reference (59th Ed., 2005).

In certain embodiments, the second active agent is administered orally, topically, intravenously or subcutaneously and once or four times a day in an amount of about 1 to about 1,000 mg, about 5 to about 500 mg, about 10 to about 10 350 mg or about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the age of the subject being treated, the severity and stage of the disease, and the amount or amounts of apremilast and any additional optional second active agents administered concurrently to the patient.

5.3 Apremilast

Without being limited by theory, it is believed that apremilast is a (+) enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl] -4-acetylaminoisoindolin-1,3-dione that has The following structure:

The apremilast can be prepared according to the procedures described in US Pat. Nos. 6,962,940; 7,208,516; 7,427,638; or 7,893,101. In a specific procedure, the apremilast can be prepared, for example, by the following procedure.

A stirred solution of 1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid ( 20 ml) at reflux for 15 h. The solvent was removed in vacuo to give an oil. Chromatography of the resulting oil gave the product as a yellow solid (1.0 g, 59% yield): mp, 144 ° C; ¹ H NMR (CDCl ^a ) 5: 1.47 (t, J = 7.0 Hz, 3H, CH ³ ), 2.26 (s, 3H, CH ³ ), 2.88 (s, 3H, CH ³ ), 3.75 (dd, J = 4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J = 7 Hz, 2H, CH ² ), 5.87 (dd, J = 4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H , Ar), 7.47 (d, J = 7 Hz, 1H, Ar), 7.64 (t, J = 8 Hz, 1H, Ar), 8.74 (d, J = 8 Hz, 1H, Ar ), 9.49 (br s, 1 H, NH); ¹³ C NMR (CDCl ^a ) 5: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11 , 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc. For C ²² H ²⁴ NO ⁷ S: C, 57.38; H, 5.25; N, 6.08. Experimental: C, 57.31; H, 5.34; N, 5.83.

Preparation of 3-aminophthalic acid: 10% Pd / C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 l) were loaded into a Parr hydrogenator of 2, 5 l under a nitrogen atmosphere. Hydrogen was charged into the reaction vessel up to 55 psi. The mixture was stirred for 13 hours, maintaining the hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a bed of celite and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was suspended in ether and isolated by vacuum filtration. The solid was dried under vacuum to a constant weight, providing 54 g (84% yield) of 3-aminophthalic acid as a yellow product. ¹ H-NMR (DMSO-d6) 5: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (br, s, 2H); ¹³ C-NMR (DMSO-d6) 5: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.

Preparation of 3-aminophthalic anhydride: a round bottom flask with 3 1-l mouths was equipped with a mechanical stirrer, a thermometer and a condenser, and was charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride ( 550 ml) The reaction mixture was heated at reflux for 3 hours and cooled to about 25 ° C and more at 0 5 ° C for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried under vacuum at room temperature to a constant weight, giving 75 g (61% yield) of acetamidophthalic anhydride 3 as a white product. ¹ H-NMR (CDCb) 5: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s , 1 HOUR).

Resolution of 2- (3-ethoxy-4-methoxyphenyl-1- (methylsulfonyl) -et-2-ylamine: A 3-liter round bottom 3-liter flask was equipped with a mechanical stirrer, a thermometer and a condenser and loaded with 2- (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -et-2-ylamine (137.0 g, 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol) and methanol (1.0 L) The stirred suspension was heated at reflux for 1 hour The stirred mixture was allowed to cool to room temperature and stirring was continued for another 3 hours at room temperature The suspension was filtered and washed with methanol (250 l) The solid was air dried and then dried under vacuum at room temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). (55.0 g) and methanol (440 mL) were refluxed for 1 hour, cooled to room temperature and stirred for an additional 3 hours at room temperature.The suspension was filtered and the filter cake washed with methanol (200 ml). The solid was air dried and then dried under vacuum at 30 ° C to a constant weight, yielding 49.6 g (90% recovery) of (S) -2- (3-ethoxy-4-methoxyphenyl) salt -1- (methylsulfonyl) -et-2-ylamin-N-acetyl-L-leucine (98.4% ee). Chiral HPLC (1/99 EtOH / 20 mM KH ² PO ⁴ @ pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm x 4.6 mm, 0.5 ml / min., At 240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).

Final preparation of apremilast: A round-bottom flask with 3 mouths and 500 ml was equipped with a mechanical stirrer, A thermometer and a condenser. The reaction vessel was charged with the N-acetyl-L-leucine salt of (S) -2- (3-ethoxy-4-methoxyphenyl) -1- (methylsulfonyl) -et-2-ylamine (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g, 58.8 mmol) and glacial acetic acid (250 mL). The mixture was refluxed overnight and then cooled to <50 ° C. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 ml x 2), saturated aqueous NaHCÜ ³ (250 ml x 2), brine (250 ml x 2) and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a binary solvent containing ethanol (150 ml) and acetone (75 ml). The solid was isolated by vacuum filtration and washed with ethanol (100 ml x 2). The product was dried under vacuum at 60 ° C to a constant weight, providing 19.4 g (75% yield) of apremilast with 98% ee. Chiral HPLC (15/85 EtOH / 20 mM KH ² PÜ ⁴ at pH 5, Ultron Chiral ES-ÜVS from Agilent Technology, 150 mm x 4.6 mm, 0.4 mL / min, at 240 nm): 25.4 min (S isomer, 98.7%), 29.5 min (^ isomer, 1.2%). ¹ H-NMR (CDCl ^a ) 5: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6, 82-8.77 (m, 6H), 9.46 (s, 1H); ¹³ C-NMR (DMSO-d6) 5: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10 , 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

5.4 Pharmaceutical compositions and dosage forms

Pharmaceutical compositions can be used in the preparation of individual dosage forms of a single unit. The pharmaceutical compositions and dosage forms may comprise an aprilant or a pharmaceutically acceptable salt or solvate thereof and a second active agent. Examples of the second optional active agents are described here ( see, for example, section 4.2.1). The pharmaceutical compositions and dosage forms may further comprise one or more vehicles, excipients or diluents.

Pharmaceutical compositions provided herein that are suitable for oral administration may be presented as discrete dosage forms, such as, but not limited to, tablets ( eg, chewable tablets), oblong tablets, capsules, and liquids ( e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical procedures well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing, Easton PA (2000).

In certain embodiments, the oral dosage forms provided herein are prepared by combining the active ingredients in an intimate mixture with at least one excipient according to conventional pharmaceutical composition techniques. Excipients can take a variety of forms that depend on the form of preparation desired for administration. Non-limiting examples of excipients suitable for use in liquid or aerosol oral dosage forms include water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of excipients suitable for use in solid oral dosage forms ( e.g., powders, tablets, capsules, and oblong tablets) include, but are not limited to starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants. , binders and disintegrating agents.

Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are used. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmacy procedures. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then the product is shaped in the desired presentation, if necessary.

For example, a tablet can be prepared by compression or molding. Pressed tablets may be prepared by compressing in an appropriate machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Non-limiting examples of excipients that can be used in oral dosage forms include binders, fillers, disintegrants and lubricants. Non-limiting examples of binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as arabic, sodium alginate, acid. alginic, other alginates, powdered tragacanth gum, guar gum, cellulose and its derivatives ( e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, ( eg, Nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof.

Non-limiting examples of suitable forms of microcrystalline cellulose include, but are not limited to materials sold as AVICEL® (microcrystalline cellulose) PH-101, AVICEL® (microcrystalline cellulose) PH-103, AVICEL RC-581® (crystalline cellulose and sodium carboxymethylcellulose), AVICEL® (microcrystalline cellulose) PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581® (crystalline cellulose and sodium carboxymethyl cellulose). Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ ® (microcrystalline cellulose) PH-103 and Starch 1500® LM (pregelatinized starch).

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talcum, calcium carbonate ( e.g., granules or powder), microcrystalline cellulose, cellulose powder. , dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 percent by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little disintegrant may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is not too high or too low to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies depending on the type of formulation and is easily discernible to those skilled in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 percent by weight of disintegrant, preferably, from about 1 to about 5 percent by weight of disintegrant.

Non-limiting examples of disintegrants that can be used in pharmaceutical compositions and dosage forms include agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilin, sodium starch glycolate, potato starch or tapioca, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

Non-limiting examples of lubricants that may be used in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol. , polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil ( e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a siloid silica gel (AEROSIL 200® (silica), manufactured by WR Grace Co. of Baltimore, MD), a coagulated synthetic silica spray (marketed by Degussa Co. of Plano, TX) , CAB-O-SIL® (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used, lubricants are typically used in an amount of less than about 1 percent by weight of the pharmaceutical compositions or dosage forms where they are incorporated.

Non-limiting examples of dosage forms include tablets; capsules, capsules such as soft elastic gelatin capsules; sachets wafers, pills, dispersions; suppositories; powder; aerosols ( eg, nasal sprays or inhalers); Liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions ( eg, aqueous or non-aqueous liquid suspensions, oil in water emulsions or water in oil emulsions), solutions and elixirs.

The composition, form, and type of dosage forms will typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients comprising a dosage form used in the chronic treatment of the same disease. These and other ways in which specific dosage forms will vary from one another will be readily apparent to those skilled in the art. See, p. eg, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton pA (2,000).

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to the manner in which the dosage form will be administered to a patient. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. The active ingredients comprising primary or secondary amines are particularly susceptible to such accelerated decomposition.

In certain embodiments, anhydrous pharmaceutical compositions and dosage forms comprising active ingredients are provided herein, since water can facilitate the degradation of some compounds. For example, the addition of water ( e.g., 5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage to determine characteristics such as half-life. or the stability of the formulations over time. See, for example, Jens T. Carstensen, Drug Stability: Principies & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. Indeed, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on a formulation can be very significant because moisture is commonly found during manufacturing, handling, packaging, storage, transportation and use of the formulations.

The pharmaceutical compositions and anhydrous dosage forms can be prepared using anhydrous or low water ingredients and low water or low humidity conditions. The pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if considerable contact with moisture is expected during manufacturing, packaging and / or storage.

An anhydrous pharmaceutical composition should be prepared and stored in a manner that maintains its anhydrous nature. Accordingly, the anhydrous compositions are preferably packaged by using known materials to prevent exposure to water so that they can be included in suitable formulation kits. Non-limiting examples of suitable packages include aluminum, plastics, unit dose containers ( eg, vials), blister packs, and sheets in hermetically sealed strips.

Pharmaceutical compositions and dosage forms are also provided herein comprising one or more compounds that reduce the rate at which an active ingredient will decompose. Such compounds, referred to herein as "stabilizers," include, but are not limited to antioxidants such as ascorbic acid, pH buffers or salt buffers. As the amounts and types of excipients, the specific amounts and types of active ingredients in a dosage form may be different depending on factors such as, but not limited to, the route by which it is to be administered to patients. However, typical oral dosage forms comprise apremilast in an amount of 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg. In particular embodiments, oral dosage forms are 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg tablets.

5.5 Delayed-release dosage forms

In certain embodiments, the active ingredients may be administered by controlled release means or by delivery devices that are well known to those skilled in the art. Non-limiting examples of controlled release means or delivery devices include those described in U. S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566. Such dosage forms can be used to provide a slow or controlled release of one or more active ingredients using, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or a combination of these to provide the desired release profile in varied proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients. In certain embodiments, unit dosage forms suitable for oral administration are provided herein which include, but are not limited to, tablets, capsules, gel capsules and tablets adapted for controlled release.

Pharmaceuticals with controlled release have a common goal of improving drug therapy over what was achieved by their uncontrolled counterparts. Ideally, the use of a controlled release preparation optimally designed in medical treatment is characterized in that a minimum of drug substance is used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations include prolonged drug activity, reduced dosage frequency, and improved patient compliance. Additionally, controlled release formulations may be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and therefore may affect the occurrence of side effects ( e.g., adverse effects). ).

Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously releases other amounts of drug to maintain this level of therapeutic or prophylactic effect during a prolonged period of time. To keep this level of drug constant in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions that include, but are not limited to, pH, temperature, enzymes, water or other physiological conditions or compounds.

6. EXAMPLES

Some embodiments are illustrated by the following non-limiting examples. The examples should not be construed as a limitation on their scope.

6.1 Biological activity of apremilast in preclinical models

Arthritic conditions are considered a Th1 autoimmune disease due to the involvement of proinflammatory cytokines, interferon (INF) ^and tumor necrosis factor (TNF) -a. The elevation of the cyclic nucleotide adenosine 3 ', 5'-cyclic monophosphate (cAMP) inhibits the release of inflammatory mediators, including TNF-a. A cellular mechanism for the inactivation of cAMP is its decomposition by cyclic nucleotide phosphodiesterase (PDE). The inhibition of PDE4 is particularly effective in inhibiting the release of inflammatory mediators. Therefore, compounds that inhibit PDE4 specifically can inhibit inflammation with a minimum of unwanted side effects.

Inhibition of TNF-a: Apremilast inhibits the production of TNF-a in PBMC (IC ⁵⁰ of 77 nM), in human whole blood (IC ⁵⁰ of 294) and in a mouse model (EC ⁵⁰ of 0.05 mg / kg ). The test procedures were those described in WO 03/080049; Muller et al., J. Med. Chem., 1996, 39: 3238; and Muller et al., Bioorg. Med. Chem. Lett., 1999, 9: 1625-30.

Inhibition of PDE4: The phosphodiesterase 4 enzyme was purified from human U937 monocytic cells by gel filtration chromatography, and phosphodiesterase reactions were carried out as described above. See Muller et al., Bioorg. Med. Chem. Lett., 1998, 8 (19): 2669-2674. Briefly, the reactions were carried out in 96-well plates of deep wells in 50 mM Tris HCl, pH 7.5, 125 mM MgC125, 1 pM cyclic adenosine monophosphate (cAMP), plus 10 nM [3H] -cAMP for 45 min at 30 ° C. The reactions were terminated by boiling, treated with 1 mg / ml snake venom and separated using AG-1X8 ion exchange resin (BioRad). The reactions consumed less than 15% of the available substrate. Apremilast inhibited PDE4 with an IC ⁵⁰ of 73.5 nM.

Selectivity of PDE4: Apremilast selectively inhibits PDE4 on PDE1 (23% inhibition at 10 pM), PDE2 (6% inhibition at 10 pM), pDE3 (20% inhibition at 10 pM), PDE5 (3% inhibition at 10 pM), PDE6 (-6% inhibition at 10 pM) and PDE7 (IC ⁵⁰ of 20.5 pM). PDE1, 2, 3 and 5 enzyme assays were prepared as described by Hidaka and Asano. Biochem Biophys Acta., 1976, 429: 485; see also Nicholsen et al., Trends Pharmaco. Sci., 1991, 12:19. The PDE6 enzyme assay was prepared according to Baehr et al., J. Biol. Chem., 1979, 254: 11669 and Gillespie et al., Mol. Pharm., 1989, 36: 773. The PDE7 enzyme assay was prepared according to Bloom and Beavo. Proc. Natl Acad Sci. USA, 1996, 93: 14188-92.

6.2 Clinical data on weight loss using apremilast

Apremilast has demonstrated the benefit of weight loss in the Psoriasic Arthritis (PSA) and Psoriasis (PSOR) Phase 2 and Phase 3 trials. Unlike the weight reduction observed as a side effect in COPD patients treated with another inhibitor of the PDE4, weight loss was observed in the treatment with apremilast for patients with an average BMI of 30 or more, which is the clinical definition of obesity. Weight loss was observed in the population of more than 4,000 patients treated with apremilast in the clinical trial programs of psoriatic arthritis and psoriasis Phase 2 and Phase 3.

Group of data from phase 3 of psoriatic arthritis (PsA)

In the Phase 3 study of psoriatic arthritis, weight loss was reported by 2 (0.3%) subjects who received placebo and 25 (1.3%) subjects who received apremilast, including 10 (1.0%) subjects in apremilast 20 mg (hereinafter «APR 20») BID group and 15 (1.5%) subjects in the BID group of apremilast 30 mg (hereinafter «APR 30»).

Phase 3 psoriasis data group (PSOR)

In the Phase 3 study of psoriasis, weight loss was reported in 1 (0.2%) subjects who received placebo and 18 (1.5%) subjects who received APR 30 mg BID.

Apremilast data group

Similar weight loss results were reported for the apremilast data set. A decrease in weight was reported during the placebo-controlled period (24 weeks) in 3 (0.2%) subjects who received placebo and 26 (0.9%) subjects who received apremilast, including 8 (0.8%) subject in the APR 20 IDB group, and 18 (1.1%) subjects in the Ap R 30 IDB group.

In the period of exposure to apremilast, a decrease in weight was reported in 17 (1.2%) subjects in the APR 20 BiD group and 36 (1.5%) subjects in the APR 30 IDB group.

Detailed analysis of weight change

Group of data from phase 3 of psoriatic arthritis (PsA)

For subjects initially treated in the Week 0 population in the PsA Phase 3 data group, the placebo group had an average weight change since the start of the 0.13 kg study compared to a change in average weight since the start of the study of -1.05 kg in the APR 20 IDB Group and -0.97 kg in the APR 30 IDB group at the end of the period controlled by Placebo or Week 24. At the end of the exposure period of apremilast, the APR 20 IDB and APR 30 IDB groups had a mean weight change since the start of the study of -1.13 kg and -1.26 kg, respectively (Table 1).

Table 1: Group of data from phase 3 of psoriatic arthritis (PsA): Change in weight from baseline

APR 20/30 IDB = apremilast 20/30 mg twice daily; max. = maximum; min. = minimum; PBC = placebo controlled; PsA = Psoriasic Arthritis

a At the end of the period, n = number of subjects with a baseline value and at least 1 baseline value. b The last reference value after the placebo-controlled period, including data up to 28 days after the last dose of the product under investigation, but excluding the observational follow-up visit.

c The last reference value after the exposure of apremilast, including data up to 28 days after the last dose of apremilast, but excluding the observational follow-up visit.

Note: data collected later than 28 days after the last dose of the product under investigation was excluded. Data were excluded in the phase of random withdrawal (weeks 32 to 52) of 28 days after starting the placebo until the apremilast resumed.

For the subjects of apremilast as a treated population, the average weight change from the beginning for the APR 20 IDB group was -1.25 kg at week 52 and -1.70 kg at week 78. For the APR group 30 IDB, the average weight change from the beginning was -1.68 kg in week 52 and -2.14 kg in week 78 (Table 2).

Table 2: Group of data from phase 3 of psoriatic arthritis (PsA): Change in weight from baseline

^

APR 20/30 IDB = apremilast 20/30 mg twice daily; max. = maximum; min. = minimum; PsA = psoriatic arthritis. a At the end of the period, n = number of subjects with a baseline value and at least 1 baseline value.

b The last reference value after the April exposure, including data up to 28 days after the last dose of the product under investigation, but excluding the observational follow-up visit.

Note: data collected later than 28 days after the last dose of the product under investigation was excluded. Data were excluded in the phase of random withdrawal (weeks 32 to 52) of 28 days after starting the placebo until the apremilast resumed.

A graphical presentation of the percentage change in weight with respect to the baseline value at the end of the treatment period for the subjects as a treated population in the Data Group of Phase 3 of PsA is provided in Figure 1. A summary of a categorical analysis of the percentage change in weight with respect to the baseline value at the end of the period during Weeks 0 to 16 of the Period of Treatment Duration and the Period of Exposure to Apremilast as a treated population is provided in Table 3. The majority of subjects who received apremilast maintained their body weight within 0% and 5% of the initial value, regardless of the duration of exposure. However, during weeks 0 to 16, a weight change of> -10% to <-5% was observed in a higher percentage of subjects who received APR 20 IDB (4.0%) or APR 30 IDB (4, 1%), compared to those who received placebo (2.0%). The observed weight loss of more than 10% during Weeks 0 to 16 occurred in 1 (0.2%) subject in the placebo group, 6 (0.7%) subjects in the APR 20 IDB group and 7 (0, 8%) subjects in the APR 30 IDB Group.

For the period of exposure to apremilast, there was a weight loss greater than 10% in 42 (4.5%) subjects in the APR 20 IDB group and 36 (3.8%) subjects in the APR 30 IDB group.

Table 3: Group of data from phase 3 of psoriatic arthritis (PsA): Summary of the percentage of change in weight with r l l l l l l r r r

APR 20/30 IDB = apremilast 20/30 mg twice daily; PsA = psoriaticarthritis.

a Placebo data based on subjects initially treated in the Week 0 population, and are provided for comparison purposes. Subjects who switched from placebo to APR are counted in the columns of the placebo and APR treatment group.

b For subjects as a treated population, data from the first 16 weeks of exposure are included regardless of when the exposure to apremilast began, that is, for subjects treated with apremilast at Week 0, study data are included Weeks 0 -16 while for subjects who are treated for the first time with apremilast at week 16, study data from weeks 16-32 are included. The end-of-period value is the last value of the posterior baseline (only during the placebo-controlled period for placebo-treated subjects), including data up to 28 days after the last dose of the product under investigation, but excluding Observational follow-up visit.

c For subjects as treated population, all data, while subjects were exposed to apremilast, regardless of when the apremilast exposure was started are included. The end-of-period value is the last subsequent reference value (while the subjects received apremilast), including data up to 28 days after the last dose of apremilast, but excluding the observational follow-up visit. Data are excluded in the phase of withdrawal from randomized treatment (weeks 32 to 52) of 28 days after starting the placebo until treatment with apremilast is resumed.

D m = number of subjects with a baseline value and at least 1 subsequent baseline value; The percentages are based on m.

Phase 3 psoriasis data group (PSOR)

For subjects initially treated in the population of week 0 in the PSOR phase 3 data group, the placebo group had a mean weight change since the start of the study of -0.02 kg, compared with a average weight change from the start of the study of -1.45 kg in the APR 30 IDB at the end of the placebo-controlled period. At the end of the April exposure, the APR 30 IDB group had an average weight change from the initial value of -1.67 kg (Table 4).

Table 4 PSOR phase 3 data group: Change in weight from baseline to end of

^

APR 30 IDB = apremilast 30 mg twice daily; max. = maximum; min = minimum; PBC = placebo controlled; PSOR = psoriasis; DE = standard deviation.

a At the end of the period, n = number of subjects with a baseline value and at least 1 baseline value. b The last reference value after the placebo-controlled period, including data up to 28 days after the last dose of the product under investigation, but excluding the observational follow-up visit.

c The last reference value after the exposure of apremilast, including data up to 28 days after the last dose of apremilast, but excluding the observation follow-up visit.

Note: data collected later than 28 days after the last dose of the product under investigation was excluded. Data were excluded in the phase of random withdrawal (weeks 32 to 52) of 28 days after starting the placebo until the apremilast resumed.

For the subjects of apremilast as a treated population, the average weight change from the beginning for the APR 30 IDB group was -1.99 kg at week 52 and -2.72 kg at week 78 (Table 5). Figure 2 shows a graphical presentation of the percentage change in weight from the beginning to the end of the treatment period for the subjects as a population treated in the data set of the PSOR phase 3.

Table 5: PSOR phase 3 data group: Change in weight from baseline by time point _________________ _____________ (Apremilast subjects treated) ______________________________ Weight, kg Change of baseline

_

_

, ±,, ±, -, ±, -, -,,, APR 30 IDB = apremilast 30 mg twice daily; max. = maximum; min = minimum; PSOR = psoriasis; SD = standard deviation.

a At a time point after the baseline, n = number of subjects with a baseline value and a value after the baseline at the time point. At the end of the period, n = number of subjects with a baseline value and at least 1 baseline value.

b The last reference value after the exposure of apremilast, including data up to 28 days after the last dose of apremilast, but excluding the observational follow-up visit.

Note: data collected later than 28 days after the last dose of the product under investigation was excluded. Data were excluded in the phase of random withdrawal (weeks 32 to 52) of 28 days after starting the placebo until the apremilast resumed.

A summary of the weight percentage change category from the beginning to the end of the period is presented in Table 6 according to the reference weight for the PSOR Phase 3 data set during Weeks 0-16, during the Weeks 0-52 and during the Expression Period of apremilast. For subjects initially treated at Week 0 and for Apremilast subjects as treated populations, the majority of subjects receiving APR 30 IDB maintained their body weight within 0% and 5% of the initial value, regardless of the duration of the exposition. However, during Weeks 0-16, a weight change of> -10% to <-5% was observed in a higher percentage of subjects receiving APR 30 IDB (11.7%) compared to placebo subjects (4.7%). The observed weight loss of more than 10% during weeks 0 to 16 occurred in 3 (0.8%) subjects with placebo and 22 (2.0%) with APR 30 subjects with IDB treated. For the period of exposure to Apremilast, a weight loss greater than 10% was observed in 65 (5.7%) APR 30 treated IDB subjects.

Table 6: PSOR phase 3 data group: Summary of the weight percentage change category

APR 30 IDB = apremilast 30 mg twice daily; PSOR = psoriasis.

a Placebo data based on subjects initially treated in the Week 0 population, and are provided for comparison purposes. Subjects who switched from placebo to APR are counted in the columns of the placebo and APR treatment group.

b For subjects as a treated population, data from the first 16 weeks of exposure are included regardless of when the exposure to apremilast began, that is, for subjects treated with apremilast at Week 0, study data are included Weeks 0 -16 while for subjects who are treated for the first time with apremilast at week 16, study data from weeks 16-32 are included. The end-of-period value is the last value of the posterior baseline (only during the placebo-controlled period for placebo-treated subjects), including data up to 28 days after the last dose of apremilast, but excluding the visit of observational follow-up

c For subjects initially treated at Week 0, all data are included while subjects are exposed to apremilast. For the subjects of apremilast as a treated column, all data were included while the subjects were exposed to apremilast regardless of when the apremilast exposure began. The end-of-period value is the last subsequent reference value (while the subjects received apremilast), including data up to 28 days after the last dose of apremilast, but excluding the observational follow-up visit. Data are excluded in the phase of withdrawal from randomized treatment (weeks 32 to 52) of 28 days after starting the placebo until treatment with apremilast is resumed.

D m = number of subjects with a baseline value and at least 1 subsequent baseline value; The percentages are based on m.

Apremilast data group

In the Apremilast data group for subjects initially treated in the Week 0 population, the placebo group had an average weight change from the start of 0.11 kg compared to an average weight change since the start of -1.01 kg in the APR 20 IDB group and -1.21 kg in the APR 30 IDB group at the end of the placebo-controlled period.

At the end of the Apremilast Exposure period, the APR 20 IDB and APR 30 IDB groups had an average weight change since the beginning of -1.09 and -1.41 kg, respectively.

Summaries of a categorical analysis of the percentage of weight change from the baseline at the end of the period during the placebo-controlled period and during the Apremilast exposure period in the Apremilast Data Set are provided in Table 7 and Table 8, respectively. For both periods of treatment, most subjects who received apremilast kept their body weight within 0% and 5% of the initial value. However, during the placebo-controlled period, a weight change of> -10% to <-5% was observed in a higher percentage of subjects who received APR 20 IDB (9.3%) or APR 30 IDB (11, 3%), compared to those who received placebo (2.8%). The observed weight loss of more than 10% during the placebo-controlled period occurred in 8 (0.6%) subjects in the placebo group, 17 (1.9%) subjects in the APR group 20 IDB and 23 (1 , 5%) subjects in the APR Group 30 IDB. For the period of exposure to apremilast, a weight loss greater than 10% was observed in 4.0% of subjects in group A ^p R 20 IDB and in 4.9% of subjects in the APR 30 IDB group.

Table 7: Apremilast data group: Summary of the percentage of weight change from baseline at the end of the period during the placebo-controlled period (subjects initially treated at week 0)

APR 20/30 IDB = apremilast 20/30 mg twice daily.

A m = number of subjects with a baseline value and at least 1 subsequent baseline value; The percentages are based on m.

Note: The placebo-controlled period includes data during the placebo-controlled period of each study. In studies PSA-002, PSA-003 and PSA-004, data are only included until week 16 for placebo-treated subjects who escaped early, while data treated until week 24 of subjects treated with apremilast are included. In these studies.

The end-of-period value is the last value of the posterior baseline (only during the placebo-controlled period for placebo-treated subjects), including data up to 28 days after the last dose of the product under investigation but excluding the visit. of observational follow-up.

Table 8: Apremilast data group: Sum of the change in weight percentage of the baseline at the end of the period during the period of exposure to a remilast of remilast treated

APR 20/30 IDB = apremilast 20/30 mg twice daily.

am = number of subjects with a baseline value and at least 1 subsequent baseline value; The percentages are based on m.

Note: Exposure to apremilast includes all data, while subjects were exposed to apremilast, regardless of when exposure to apremilast began. In the PSOR-008 and PSOR-009 studies, data collected in the random withdrawal phase (weeks 32 to 52) were excluded 28 days after starting the placebo and before resuming the apremilast. The duration of placebo treatment in the withdrawal phase is excluded. of exposure to apremilast.

The end-of-period value is the last subsequent reference value (while the subjects received apremilast), including data up to 28 days after the last dose of apremilast but excluding the observational follow-up visit.

The above data indicate that apremilast treatment provides a weight loss benefit to patients with an average BMI of 30 or more, which is the clinical definition of obesity.

Claims (15)

1. A compound for use in a procedure to treat or control obesity or overweight, which comprises administering an effective amount of the compound orally to an obese patient, where the compound is (+) - 2- [1- Stereomerically pure (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione or one of its pharmaceutically acceptable polymorphs, salts or solvates. 2. The compound for use according to claim 1, wherein the process comprises the administration of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3- Says stereomerically pure once or twice a day. 3. The compound for use according to claim 2, wherein the process comprises the administration of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindindin-1,3- dione stereomerically pure in an amount of approximately 10 mg, 20 mg, 30 mg or 40 mg twice daily. 4. The compound for use according to claim 1, wherein the stereomerically pure (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione comprises more from about 90% by weight or more than about 95% by weight or more than about 96% by weight or more than about 97% by weight or more than about 98% or more than about 99% by weight of the (+) isomer based on the total weight of the compound. 5. The compound for use according to claim 1, wherein the process comprises the administration of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3- Says stereomerically pure once or twice a day. 6. The compound for use according to claim 5, wherein the tablet comprises a dose of 10 mg, 20 mg, 30 mg or 40 mg of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2 -methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione stereomerically pure. 7. The compound for use according to claim 6, wherein the tablet comprises a dose of 10 mg of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfodylethyl] -4-acetylaminoisoindindin-1 , 3-dione stereomerically pure; or where the tablet comprises a 20 mg dose of (+) - [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfodylethyl] -4-acetylaminoisoindindin-1,3-dione stereomerically pure; or where the tablet comprises a dose of 30 mg of (+) 1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfodylethyl] -4-acetylaminoisoindindin-1,3-dione stereomerically pure; or where the tablet comprises a dose of 40 mg of (+) 1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfodylethyl] -4-acetylaminoisoindindin-1,3-dione stereomerically pure. 8. The compound for use according to claim 6, wherein the tablet further comprises lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. 9. The compound for use according to claim 8, wherein the tablet further comprises red iron oxide, red iron oxide and yellow iron oxide, or red iron oxide, yellow iron oxide and black iron oxide. 10. The compound for use according to claim 1, wherein the method further comprises administering to the patient a therapeutically effective amount of one or more second active agents. 11. The compound for use according to claim 10, wherein the one or more second active agents are medicaments for treating obesity or overweight, where optionally the second active agent is orlistat, lorcaserin, topiramate, phentermine, diethylpropion, phendimetrazine, benzfetamine or A combination of them. 12. The compound for use according to claim 1, further comprising weight reduction measures of dietary habit change, exercise program, psychological support program or a combination thereof. 13. The compound for use according to claim 1, wherein the obesity is recurrent or refractory to a previous treatment. 14. The compound for use according to claim 1, wherein the process further comprises administering (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindindin-1,3- stereomerically pure dione, substantially free of any salt or solvate form of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione. 15. The compound for use according to claim 1, wherein the process further comprises administering a pharmaceutically acceptable salt or solvate of (+) - 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- Stereomerically pure acetylaminoisoindindin-1,3-dione.